title: Treatment rationale and study design for a randomized, double-blind, placebo-controlled phase II study evaluating onartuzumab (MetMAb) in combination with bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal cancer.
abstract: BACKGROUND
  Dysregulation of the hepatocyte growth factor (HGF)/MET pathway is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in patients with metastatic colorectal cancer (mCRC). Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. We present the treatment rationale and protocol for an ongoing randomized multicenter placebo-controlled phase II study designed to evaluate the efficacy and safety of MetMAb combined with bevacizumab and mFOLFOX-6 (5-fluoruracil, leucovorin, and oxaliplatin).
  
  
  METHODS
  Eligible patients with previously untreated mCRC are randomized 1:1 to either mFOLFOX-6 combined with bevacizumab and placebo followed by 5-fluorouracil/leucovorin plus bevacizumab and placebo or mFOLFOX6, bevacizumab plus MetMAb followed by 5 FU/LV, bevacizumab, and MetMAb. The primary end point of this study is progression-free survival (PFS) in the intent-to-treat (ITT) population. Secondary end points include overall survival (OS), objective response rate, and safety. Subanalyses will be performed to evaluate the effect of MET receptor expression on study primary and secondary end points. Correlative studies will be performed on tissue- and blood-derived biomarkers related to both HGF/MET signaling and other associated pathway markers.
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA. jbendell@tnonc.com
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ervin
authors.forename: David
authors.initials: D
authors.lastname: Gallinson
authors.forename: Jaswinder
authors.initials: J
authors.lastname: Singh
authors.forename: James A
authors.initials: JA
authors.lastname: Wallace
authors.forename: Mansoor N
authors.initials: MN
authors.lastname: Saleh
authors.forename: Marcy
authors.initials: M
authors.lastname: Vallone
authors.forename: See-Chun
authors.initials: SC
authors.lastname: Phan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hack
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D004311:Double-Blind Method; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D012107:Research Design; D015996:Survival Rate; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; C584058:onartuzumab; D002955:Leucovorin; D005472:Fluorouracil
keywords: HGF/MET pathway; Metastatic colorectal cancer; Onartuzumab; Vascular endothelial growth factor (VEGF)